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Cancer cells exchange leaders during invasion (PNAS)

A new study has found that cancer cells appear to exchange leading roles as they migrate out of a tumor in the early stages of invasion, or metastasis, of other sites in the body. Metastatic cancer accounts for more than 90% of cancer-related deaths.

A team led by Robert Austin, professor of physics at Princeton University, found that individual cancer cells take turns as trailblazers when they carve their way through the dense wall — known as the extracellular matrix — that stands between a tumor and the blood vessels which can carry the cells to other parts of the body.

The researchers also found that the cells leave the tumor in search of food, since cells that had plenty of available nutrients did not migrate. The finding reinforces the hypothesis that metastasis occurs when tumors become so densely packed that blood vessels cannot penetrate the interior and cancer cells must migrate to survive.

The researchers included first author Liyu Liu of the Chinese Academy of Sciences; Guillaume Duclos of the National Center for Scientific Research in Paris; Bo Sun, Jeongseog Lee, Amy Wu, Howard Stone and James Sturm of Princeton University; Yoonseok Kam and Robert Gatenby of H. Lee Moffitt Cancer Center in Tampa; and Eduardo Sontag of Rutgers University. The article appeared in the Proceedings of the National Academy of Sciences.

To study cancer cell behavior, the researchers constructed a small chamber with three compartments arranged like floors in an apartment building. On the bottom floor was a well of glucose, the preferred food for metastatic cells. The middle floor contained a dense layer of collagen, a protein that makes up the extracellular matrix that surrounds tumors. On the top floor they placed metastatic cancer cells, which were labeled with fluorescent dye for visibility. They trained a microscope and camera on the chamber.

Through the microscope, the researchers filmed the cancer cells as they moved down through the chamber toward the glucose. The researchers found that a single cell would become the leader for some time, then drop back as another cell took the lead in what the authors term a “collective invasion strategy.” They also found that the collagen was pushed aside, leaving a wake in which cells behind the leader could travel.

Because the collagen is very dense, the cells must expend a lot of energy to reach the glucose, and indeed the researchers found that cells without a need for glucose did not bother to burrow down into the collagen. The researchers used collagen with a density similar to that of human breast tissue.

The study adds to the growing understanding of metastasis and could serve to assist researchers in developing strategies for its prevention.